Abstract

Background Although millions of people with schizophrenia live in
betel chewing regions, the effects of betel chewing on their symptoms are
unknown. Betel nut alkaloids include potent muscarinic cholinomimetics: recent
research suggests that these agents may be therapeutic in schizophrenia.

Aims To compare the primary and extrapyramidal symptom profiles and
substance-using habits of betel chewing v. non-chewing people with
schizophrenia.

Method A cross-sectional study of 70 people with schizophrenia.
Symptom ratings measured by the Positive and Negative Syndrome Scale (PANSS)
and Extrapyramidal Symptom Rating Scale (ESRS), and demographic and
substance-use data, were compared for 40 chewers and 30 non-chewers of betel
nut.

Results Betel chewers with schizophrenia scored significantly lower
on the positive (P=0.001) and negative (P=0.002) sub-scales
of the PANSS than did non-chewers. There were no significant differences in
extrapyramidal symptoms or tardive dyskinesia.

Conclusions Betel chewing is associated with milder symptomatology
and avoidance of more harmful recreational drugs. These initial results
indicate that longitudinal research is merited.

‘Betel chewing’ describes the practice of masticating a quid of
ingredients, including the seed of the Areca catechu palm (betel
nut), the leaf of the creeping vine Piper betle and lime, usually in
the form of burnt shell or coral. Betel nut is humanity's fourth most widely
used drug after nicotine, ethanol and caffeine, and is chewed by millions of
people living between the east coast of Africa and the western Pacific
(Marshall, 1987).

Nine alkaloids constitute the active ingredients of betel nut
(Farnworth, 1976), the most
abundant of which is arecoline - a potent muscarinic agonist that rapidly
crosses the blood-brain barrier and induces a range of parasympathetic effects
(Asthana et al, 1996).
Such cholinergic agents are again receiving attention as potential treatments
for psychosis (Bodick et al,
1997; Tandon,
1999). Our principal hypothesis is that the muscarinic action of
betel nut may exert a beneficial effect on the symptoms of people with
schizophrenia. Since millions of people with schizophrenia live in
betel-chewing regions, an increased understanding of the interaction between
betel chewing and schizophrenia should benefit clinical treatment.

METHOD

Research setting

The study was conducted in the Republic of Palau (population 17 000), the
westernmost island group in Micronesia. As betel chewing is an integral
cultural activity practised by more than 70% of the population
(Ysaol et al, 1996;
Futterman & Lyman, 1998),
Palau is an ideal study context, combining a well-described and accessible
schizophrenia population (Myles-Worsley
et al, 1999) and a modern American-style health
service.

Subjects

Following ethical approval, the study was carried out at the Belau National
Hospital between June and October 1998. The inclusion criteria were chronic
schizophrenia or schizoaffective disorder (with mainly schizophrenic course),
with an established DSM-III or DSM-IV (American Psychiatric Association,
1980,
1994) diagnosis.

Seventy-six informed and consenting out-patients, all indigenous Palauans,
completed the study and were paid for their participation. Five subjects with
bipolar disorder and one with acute schizophrenia were excluded, leaving a
final pool of 70 subjects (49 men and 21 women). Fifty-four subjects were
being treated with either haloperidol or fluphenazine (mainly by depot
injection) and 48 were receiving anticholingeric medication. No participants
were treated with atypical medications.

A recently completed genetic epidemiological study had identified and
diagnosed 160 people with ‘strictly defined’ schizophrenia in
Palau (Myles-Worsley et al,
1999). A number of these people were now deceased or ‘
off-island’, leaving 122 people from the original group; the
study sample therefore includes about 57% of the known Palauan schizophrenia
population.

Fifty-two subjects (74.3% of the sample) chewed betel nut. However, this
group included a proportion of casual users. The ‘serious’ betel
chewer carries a kit of ingredients and is readily distinguishable from the ‘
social’ user, who does not carry chewing paraphernalia but
accepts a quid from peers in social situations. The casual users were included
in the non-chewing group. After local advice on defining ‘casual
user’, an arbitrary cut-off point was made at two or fewer betel nuts
per day as the criterion for inclusion in the non-chewing group. This cut-off
produced a chewing group of 40 and a non-chewing group of 30.

A subgroup of 16 subjects (10 chewers and 6 non-chewers) were not receiving
antipsychotic pharmacotherapy and were used as a comparison group to control
for the effects of medication.

Instruments

The symptomatology of betel chewers was compared with non-chewers using the
Positive and Negative Syndrome Scale (PANSS;
Kay et al, 1992), the
Extrapyramidal Symptom Rating Scale (ESRS;
Chouinard & Ross-Chouinard,
1979) and a self-report questionnaire of substance-using habits.
In conjunction with demographic details, the substance-use questionnaire asked
about consumption of betel nut, cigarettes, alcohol and marijuana.
Self-reports were supplemented with reference to chart histories of substance
misuse and consultation with case workers.

All rating was carried out by R.J.S. To avoid rater bias, the interviewer
was blind to the chewing status of subjects until symptom rating was
completed. The test batteries were conducted in English with the assistance of
the study participant's case worker - either a psychiatric nurse or social
worker. English is the language of instruction in Palauan schools and all
subjects spoke English with varying degrees of fluency. The case worker helped
each participant to complete the substance-use questionnaire and acted as
interpreter when required during the PANSS interview and ESRS assessment that
followed. Background information on the participant's social functioning
required for the PANSS was obtained from the participant's chart, case worker
and family.

Palauan case workers were consulted on the range of PANSS items as they
related to each subject, particularly delusional content, communication and
cognitive agility, and interpretation of affect. The Structured Clinical
Interview for the PANSS (SCI-PANSS; Kay
et al, 1992) was translated into Palauan, then
back-translated into English to provide a transcultural reference text for the
rater and case workers. The westernised ‘similarities’ and ‘
proverbs’ items of the ‘abstract thinking’ section of
the PANSS were substituted with Palauan expressions and proverbs.

Statistical tests

Differences in scale scores between sample groups were compared using the
independent samples t-test. Non-parametric data were assessed using
the χ2-test and the independent samples Mann-Whitney
U-test. Correlations between continuous variables were assessed using
Pearson's r. All tests were two-tailed. The 95th percentile (0.05)
was considered the minimum level of statistically significant difference in
all tests.

RESULTS

Demographic and clinical data by chewing status

Chewers and non-chewers were significantly different in the proportions who
had ever married, in mean number of off-spring and mean age at first admission
to hospital (Table 1). With the
exception of age at first admission, these differences are an artefact of the
uneven gender distribution in the non-chewing group (87% male). The sample
exhibits characteristic gender differences in marital status and number of
children: 48% (10) of the women were or had been married, v. 10% (5)
of the men (P=0.002); and women averaged 2.3 (1.7 s.d.) children
v. 0.5 (1.1 s.d.) children per man (P<0.001). However,
there were no significant differences in marital status or number of children
in intra-gender comparisons (data not shown).

Among chewers the average betel nut consumption was 10.6 (5.7 s.d.) whole
nuts (18.8 (11.1 s.d.) quids) per day. This figure is probably conservative,
as an uncharacteristic dry season, attributed popularly to El
Niño, resulted in a shortage of betel nut
over the first few months of the study period: 29 members of the chewing group
(72.5%) said that they were chewing less frequently than usual.

With the exception of the positive and negative sub-scales
(r=0.18), the PANSS sub-scales and total score are significantly
intercorrelated. Therefore, although all PANSS sub-scale and symptom cluster
data are reported with associated P values, statistically valid scale
comparisons should be limited to those between the positive and negative
sub-scales.

The mean PANSS scores for the chewing group were significantly lower than
those for the non-chewing group on the positive, negative and general
psychopathology sub-scales, as was the total score
(Table 2). This trend was
repeated in symptom cluster measurements of thought disturbance, paranoid
belligerence and anergia. Scores on the ESRS of extrapyramidal symptoms (EPS)
and tardive dyskinesia (TD) were not significantly different between the two
groups. In comparison to a normative United States PANSS sample of 240
medicated North American patients with schizophrenia
(Kay et al, 1992),
the positive and negative scale scores of non-chewers were ‘
average’, and those of chewers were ‘slightly below’
to ‘below average’, suggesting that these group-symptomatology
profiles are broadly comparable transculturally.

In the unmedicated subgroup, chewers scored significantly lower on the
scale for negative symptoms and the anergia symptom cluster, on the general
psychopathology scale and in total score
(Table 3). There were no
significant between-group differences in positive symptoms. The unmedicated
chewers consumed more betel nut than medicated chewers (24.2 v. 18.8
quids/day) with an associated increase in estimated chewing time from 4.7 to 6
h/day (Table 1). No significant
differences in EPS or TD scores emerged between the two groups.

A significant negative correlation between cigarette smoking and betel
chewing was found, that is, subjects tended to be either exclusively chewers
or smokers (Table 4). However,
most betel chewers included tobacco as an ingredient of their chewing quid,
resulting in a majority of subjects (91.4%) consuming tobacco either as part
of a chewing quid or as smoked cigarettes. Smokers, none the less, consumed
more tobacco, at an average of 13.8 cigarettes/day v. 6.1 for those
who included tobacco in the betel quid.

Alcohol and marijuana consumption were not significantly related to PANSS
symptom scores. The relationship between cigarette smoking and schizophrenia
symptoms was a reversal of the betel data: the total PANSS score of the
smoking group was significantly higher than that of the non-smoking group
(t=3.13, P=0.002).

DISCUSSION

Although it has been previously suggested that betel nut alkaloids should
be considered in the search for pharmacological treatments for schizophrenia
(Smythies, 1977), to our
knowledge this suggestion has not been pursued and this is the first study to
investigate the effects of betel nut directly on the symptoms of people with
schizophrenia.

Our results indicated that betel chewing is associated with less severe
symptoms of schizophrenia as measured by the PANSS. Chewers scored
significantly lower than non-chewers on the positive and negative symptom
measures of the PANSS. The symptom score differences between groups were
modest for the total group and balanced between positive and negative
symptoms. When only subjects not receiving medication were considered, the
group difference was substantial, mainly for negative symptoms. Among all
subjects, the group total scores of chewers were significantly lower than
those of non-chewers (60.5 v. 77.3, t= -4.1,
P≤0.001) and among unmedicated subjects the difference in mean
total PANSS score between chewers and non-chewers was dramatic (57.7
v. 84.0, t= -2.3, P=0.04).

Muscarinic agonists in schizophrenia

The main study hypothesis, that betel chewing may exert a beneficial effect
on the primary symptoms of schizophrenia, is supported by these results, and
the muscarinic agonist action of the most abundant betel nut alkaloid,
arecoline (Farnworth, 1976),
provides the most promising pharmacological explanation for this effect.

Despite ambiguous results in early research
(Davis et al, 1978), a
number of researchers propose that cholinergic agents may modulate
dopaminergic hyperactivity and prevent the emergence of positive symptoms
(Friedhoff & Alpert, 1973;
Davis et al, 1978;
Tandon & Greden, 1989;
Tandon, 1999). Research
suggests that muscarinic agonist derivatives of arecoline may exert an
atypical-like action, ameliorating both negative and positive symptoms. Bodick
et al (1997) report
that the selective M1 agonist xanomeline, a thiadiazole derivative
of arecoline (Moltzen & Bjornholm,
1995), produced dose-dependent reductions in delusions,
hallucinations and other psychotic behaviours in a clinical trial with
patients diagnosed with Alzheimer's disease. Shannon et al
(1998) performed preclinical
rodent studies assessing the use of xanomeline as an antipsychotic and
produced results consistent with the performance of atypical agents. They
conclude that “xanomeline may provide a novel approach to the treatment
of psychosis with potential for a rapid onset of action, efficacy against
positive and negative symptoms, and with little or no liability to produce
extra-pyramidal side-effects” (see also studies on other muscarinic
agents by Bymaster et al
(1998) and Shannon et
al (1999)).

Betel nut arecoline may have similar effects to those of its derivatives
described above. Betel chewers hold the betel quid in the buccal cheek cavity,
utilising an absorption route that avoids first-pass metabolism and
maintaining betel alkaloids in the blood stream for extended periods. The
non-selective agonist action of arecoline may exert a crude atypical-like
antipsychotic effect, in conjunction with the parasympathetic effects
routinely tolerated by habitual users. Such an action may explain the
favourable effect on negative symptoms and the generally mild EPS and TD among
betel-chewing subjects with schizophrenia.

Extrapyramidal symptoms and tardive dyskinesia

Extrapyramidal symptoms resulting from betel nut consumption have been
reported previously (Deahl,
1989). As discussed above, no significant differences emerged in
ratings of EPS or TD between chewers and non-chewers. Additionally, no
significant differences emerged in dosages of neuroleptic or anticholinergic
medication.

Despite compliant (i.e. mainly depot) long-term neuroleptic medication with
substantial dosages for many subjects, symptoms of TD were fairly infrequent
among the study participants. Unambiguous TD symptoms, such as choreoathetoid
or bucco-lingual movements, were seen in only 7 of the 70 participants (10%).
In comparison, a previous analysis of 76 studies (n=39187) has
reported a TD prevalence of 24.2% cross-culturally
(Yassa & Jeste, 1992).

Other substances

In accordance with findings reported elsewhere
(Chong & Choo, 1996), our
results show that smokers' PANSS scores were significantly higher than
non-smokers'. The possibility that the favourable association between PANSS
score and betel chewing is an artefact of non-smoking is unlikely, because
most chewers consumed tobacco in their quid.

Similarly, the finding that betel nut tends to be used to the exclusion of
other substances is of interest, but is unlikely to explain the favourable
association between betel chewing and milder symptoms of schizophrenia, as
neither marijuana nor alcohol consumption were significantly related to group
PANSS scores.

Social variability

Betel chewing is a social activity in Micronesia and it may be associated
with milder symptomatology simply because the practice itself is indicative
of, or marks a return to, ‘normal’ social functioning
(Wilson, 1979). However, a
social functionality explanation for group differences in scale scores is not
supported by the data, since there were no significant chewing v.
non-chewing group differences in regard to demographic indicators of social
functionality - marital status, number of children, living situation or
employment status. Additionally, an assessment of social functioning is
implicit in the structure of the PANSS instrument via input from family
members and case workers. However, a suitable social functioning instrument is
recommended in any subsequent research to more directly clarify associations
between social functioning and betel chewing.

CLINICAL IMPLICATIONS AND LIMITATIONS

CLINICAL IMPLICATIONS

In a sample comprising more than half of the known schizophrenia
population in Palau, the symptoms of betel chewers as measured by total
Positive and Negative Syndrome Scale (PANSS) scores were significantly milder
than those of non-chewers. The differences were most dramatic in a small group
of unmedicated subjects.

Chewing was not significantly associated with increases in
extrapyramidal symptoms (EPS), despite the cholinergic effects of betel
chewing. However, EPS may have been masked in medicated subjects, as the
majority were treated with anticholinergic medication.

Betel chewing was not associated with the use of alcohol or marijuana
and was inversely related to cigarette smoking.

LIMITATIONS

The relationship between milder symptomatology as measured by the PANSS
and betel chewing is associative rather than causal. The study results
highlight the need for pharmacokinetic/dynamic research of betel nut alkaloids
via the buccal route, in conjunction with further research on the muscarinic
cholinergic aspects of schizophrenia.

The cross-sectional study design has methodological limitations and a
prospective design is recommended for subsequent research.

The analysis of social factors was limited to demographic data and the
PANSS instrument. A suitable social functioning instrument is recommended in
subsequent research, to clarify associations between social functioning and
betel chewing.

Acknowledgments

The authors thank the participating subjects and the many people
instrumental in the completion of this study. In New Zealand: Dr J. Collier
and Dr A. Futterman-Collier, M. Harrison, Professor R. Kydd, Professor R.
Miller, Dr G. Robinson. In Micronesia: P. Aribuk, Dr G. Dever, A. Franz, Rev.
F. Hezel, G. Johanes, H. Masayos, Dr M. Myles-Worsley, H. Ngiralmau, A. Lyman,
D. Patris, Dr A. Polloi, Senator Peter and Akiko Sugiyama, Minister M. Ueda
and the staff at Belau National Hospital. This research was supported by
grants from the New Zealand Schizophrenia Fellowship and The University of
Auckland Research Committee. This study is dedicated to the memory of Dr A.
Polloi.